This application relates to the localized treatment of disease in hollow tubular organs, such as blood vessels, and other tissue lumens. The treatment regime involves the introduction of a therapeutic agent into a region of the tissue lumen defined by two expansile members. In particular, the application relates to the use of this technique to perform "bloodless angioplasty" in blood vessels having flow restrictions due to atherosclerotic plaque.
Within the bodies of animals, including man, there exist those organs or structures having hollow or tubular geometry, for example blood vessels such as arteries or veins, the gut and the bladder. In addition, there exist many "solid" organs which possess true spaces such as cavities, cavernous sinuses, lumens etc. These "solid" organs include the heart, liver, kidney and pancreas. Finally disease processes (e.g., necrotic tumors) and traumatic injury may create spaces within otherwise solid organs.
The lumens afforded by these various types of spaces can be affected by a variety of disease processes. For example, the lumen may be occluded thus limiting or preventing flow through the lumen. Since the lumen of many hollow organs serves a vital function, e.g., the transit conduit for blood, urine, bile or food, this restriction of flow through the lumen is detrimental. A particular example is the development and growth of an occluding atheroma (atherosclerotic plaque) in an artery, thereby reducing the blood flow through the artery.
In many cases, the wall of a tissue lumen has a significant barrier function as well as acting as a conduit for fluids. As an example, in a blood vessel, the "intima" or endothelial lining layer separates overflowing blood from the underlying middle or "media" portion of the vessel. Since the media is highly thrombogenic this separation is necessary to avoid clotting of the blood in normal blood vessels. Further, the media, if exposed to overflowing blood as a result of violation of the intimal barrier may be stimulated by platelets and macrophages in the blood, leading to smooth muscle cell proliferation and a regeneration of the stenosis. Disease conditions, such as advanced ulcerated atherosclerotic lesions, and in some instances intervention techniques, can disrupt this barrier layer leading to local blood clotting, inflammation and diffusion of growth stimulating factors such as platelet derived growth factor (PDGF), interleukin-1, and macrophage-derived growth factor (MDGF) into the media with subsequent activation, migration and proliferation of smooth muscle cells in the intima leading to a local buildup and regrowth of the stenosis.
Disease processes can also lead to the alteration of the structure and/or function or the tissue surrounding the lumen. For example, part of the tissue wall may be replaced by a cancerous/tumorous region or by an inflammatory zone. In advanced atherosclerosis, the vessel wall is replaced with lipid and inflammatory cell infiltrates, newly proliferated smooth muscle cells, fibrotic collagen and other connective tissue and dense calcium deposits. This replacement dramatically alters vessel function preventing (1) vessel vasomotion, i.e., the ability dilate or contract thereby altering blood flow based on organ metabolic demands; (2) normal flux in cellular nutrients into and through the vessel, i.e., glucose and oxygen as well as outflow of metabolic breakdown products/wastes; (3) normal release of downstream acting vasoreactive substances, i.e., endothelial derived relaxation factor (EDRF); and (4) normal metabolism of locally acting growth substances such as PDGF made by endothelial cells, thereby altering local vessel wall growth control and repair capabilities.
Further, even if there is not a change in the apparent makeup of the tissue surrounding the lumen, the metabolism of these cells may change. Thus, the production of required mediators such as growth factors and hormones may be disturbed. This also happens in atherosclerosis, where trans-vessel wall flow of nutrients, oxygen, lipid compounds, and growth factors are typically altered.
Although the types of problems which can occur in hollow organs and tissue lumens are generally recognized, the treatment regimes available generally attempt to treat the symptom rather than the underlying cause. This has a number of drawbacks, as can be illustrated using atherosclerosis as an example.
In atherosclerosis, the overall problem is the progressive build-up of an atheroma or atherosclerotic plaque at a focal location on an artery wall. The plaque is a complex of multi-component three dimensional structure composed of proliferating smooth muscle cells, stimulated macrophages and other inflammatory cells, chemically modified lipid components, i.e., cholesterol, oleate:linoleate esters, stiff connective tissue, i.e., collagen, and calcium. The distribution of plaque in the vessel wall is such that the bulk of the disease mass resides as an obstructing growth or "bulge" within the vessel lumen. This leads to reduced blood flow across the point of the plaque and subsequent reduced downstream blood flow. If such a restriction of flow occurs in the vital arterial beds, e.g., the coronary arteries in the heart or the carotid artery in the neck, the reduction of blood flow can lead to angina in the heart or a transient ischemic attack (TIA) in the brain. Complete flow cut-off will lead to heart attack or stroke, respectively.
Treatment for atherosclerosis has progressed from coronary artery bypass grafting (CABG) to catheter based techniques such as percutaneous transluminal coronary angioplasty. (PTCA) Thus, the state of the art has gone from merely by-passing the problem region to actually attempting to relieve the effects of the obstruction by direct attack and dilatation of the lesion. These attempts have led to the development of various catheter designs and treatment techniques. For example, U.S. Pat. No. 4,636,195 to Wolinsky describes the use of a catheter with two occluding balloons and a conduit for supplying a solubilizing agent to dissolve the plaque. A central balloon is included to force the solubilizing agent into the plaque. U.S. Pat. No. 4,610,662 of Weikl et al. describes a catheter which isolates the diseased region using a catheter having two expandable balloons and then introduces a chemical, such as digestive enzymes, for dissolving the plaque between the balloons. A similar approach to the treatment of gall stones is disclosed in U.S. Pat. No. 4,781,677 to Wilcox.
These approaches, however, like the basic technique of angioplasty itself, make no attempt to address the underlying pathophysiology that is operant or to otherwise biomanipulate the lesion. Thus, there is no effort to induce lesion regression or resorption or the full disappearance of the lesion with healing and replacement of the diseased wall segment with a healthy wall segment with normal vessel components and function. The present invention fills this need, by providing for the focal administration of therapeutic agents to a diseased region, either alone or in conjunction with a physical attack (such as PTCA) on the diseased region.